`
`.19.
`
`|11| Patent Number:
`
`5,835,983
`
`Bitter ct al.
`
`|45] Date of Patent:
`
`Mar. 23, 1999
`
`US005885983A
`
`OTHER PUBI .ICATI ONS
`
`I"-rigola J et al. J. Med. Chem. 36(7), 801-10, 1993.
`Nisalo D and 1'-‘rigerio M. J. Ileterocycl. Chem. 22(4),
`961-3, 1985.
`Masuda K et al.'I‘akeda Kenkyusho IIo. 31(4), 453-9, 1972.
`Hirata M et al. 'l‘iIkeda Kcnkyuslto I-Io. 31(2), 206-20, 1972.
`Chen '1‘! el al. Bull. Chem. Soc. Jap. 41(3), 712-6, 1968.
`Melloni P et al. J. Med. Chem. 22(2), 183-91, 1978.
`Bulleid & 1-‘rccdman, Nature 335, 649-651 (1988). “Defec-
`tive eo—translational formation of disulphide bonds in pro-
`tein clisulphideisomerase—deficient rnicrosomes“.
`Koivu ct al., J. Biol. (Them. 262, 6447-6449 (1987). “A
`Single Polypeptide Acts Both as the [3 Subunit ol‘ Prolyl
`4-1-Iydroxylase and as a Protein 1)is11lficle—lsomerase*”.
`Kane & Ilavcl in the Metabolic Basis of Inherited Disease,
`Sixth Edition, 1139-] 164 ( 1989). "Disorders ofthe Diogen-
`esis and Secretion of Lipoproteins Containing The B Apo-
`lipoproteins”.
`Schaefer et al., (Ilin. (Shem. 34, 1-39-1312 (1988), “Genetics
`and Abnormalties in Metabolism o1I.ipoproteins”.
`Drayna et 11]., Nature 327, 632-634 (1987). “Cloning and
`sequencing 111' human cholesteryl ester
`transfer protein
`cl)N1\."’.
`
`Pihlajaniemi et al., EMBO J. 6, 64}649 (1987). "Molecular
`cloning of the |3—subunit of human pro1yl—4-hyclroxylasc.
`This subunit and protein disulphide isomerase are products
`of the same gene".
`Yamaguehi et al., Biochem. Biophys. Res. Comm. 146,
`1485-1492 (1987). “Sequence of .Vlembrane-Associated
`Thyroid Hormone Binding Protein From Bovine Liver: Its
`Identity with Protein Disulphide Isomerase".
`F.dman et al., Nature .317, 267-270 (1985). Sequence of
`protein disulphide isomerase and implications of its rela-
`tionship to thioredoxin.
`Kan el 211., Connective 11581.16 Research 18, 157-174 (1 988).
`“Isolation of cDNA Clones and Genomic DNA Clones of
`
`[1-Subunit ol‘ Chicken Proplyl 4-IIydroxylase*”.
`Wetterau, J. et al., Biochem 30, 9728-9735 (1991). "Protein
`Disulfide Isomerase Appears Necessary To Maintain the
`Catalytically Active Structure of the Microsomal Triglycer-
`ide 'l'ran.sl‘er Protein".
`
`(List continued on next page.)
`
`t"r1.'mr:r__v 1:'x(1711i1te1'—l.ivelyn lluang
`A11r)rr1ey, Agent’, 07' H7'm—l3urton Rodney
`
`|57|
`
`ABS'1'RAC'l'
`
`Compounds are provided which inhibit microsomal triglyc-
`eride transfer protein and thus are useful for lowering serum
`lipids and treating atherosclerosis and related diseases. The
`compounds have the structure
`
`0
`1:5’ \
`R
`%N —(c11g),,
`
`wherein 111 to 115, Q, and X are as defined herein.
`
`15 Claims, N0 Drawings
`
`54]
`
`INHIll.I'I‘()RS ()l" MICROSUMAI.
`'l"RIGI.YCI£RIl)lC TRANSl‘l€R l’R()TIiIN AND
`ME'l'H()l)
`
`75]
`
`Inventors: Scott A. Biller, Hopewell; .lohn K.
`Dickson, J12, Eastampton, both of NJ.
`
`73] Assignee: Bristol-Myers Squibb Company,
`Princeton, NJ.
`
`21] Appl. No.: 847,775
`
`22]
`
`I’i11;d:
`
`Apr. 23, 199'?
`
`Related U.S. Application Data
`
`60]
`
`l’1'ovisio11al application No. 6t11'(lI7,254, May 11}, 1996.
`
`51]
`
`Int. cu‘ ...................... .. /\6lK 311395; /\ti'tK 31141;
`A61K 311435; A6t1<_ 311495; C07D 205104
`5141210; 51412355; 5141243;
`52] U.S. Cl.
`5141252; 5141290; 5141292; 5141314; 5141340;
`5141357; 5141374; 5141373; 5141397; 5141403;
`5141405; 5141414; 5481180; 5451215; 5481248;
`5481314; 548_.«'352.5; 54313541; 5481457;
`5451930; 5481935; 540'.-'85; 5451111; 5451155;
`5451159; 54512581; 5441168; 5441235;
`5441238; 5441277; 5441405; 5441407
`|58| Field of Search ................................... .. 5481930, 935,
`5481180, 352.5, 354.1, 457, 215, 248, 314;
`5451155, 159, 255.1, 35, 111; 5441233,
`168, 405, 407, 235, 277; 5141340, 314,
`357, 403, 252, 397, 235.5, 290, 292, 243,
`255, 374, 378, 405, 414, 210
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMFNTS
`
`................... .. 26ll"293.62
`11111975 Cavalla ct a1.
`3_,9ltJ_,93l
`4241244
`11111978 Melloni
`....... ..
`-1,123,527
`.. 4241267
`911981 Bcngtssoii ct al.
`..
`4,289,781
`111983 Boix—[gleasias et al.
`.. 4241267
`4,367,232
`5141212
`311986 Tahara et al.
`.
`4,576,940
`411986 Iahara et at.
`.
`5141212
`4,581,355
`811986 Pierce .......... ..
`5141323
`-’l,6[J7,0-42
`..... ..
`511989 Picciola et :11.
`5441391
`4,826,975
`611991 V"ega—No\1erol:1 et at.
`5461224
`5,026,858
`711991 Dcsai et al.
`5141321
`5,028,616
`711991 Baldwin et al.
`5141318
`5,032,598
`211992 Pinol
`........... ..
`51412111
`5,087,621
`311992 Desai et :11.
`5141324
`5,098,915
`711992 Pan ct al.
`.... ..
`5141460
`5,130,333
`211993 Peglion E1 711.
`5141319
`5,189,045
`511993 Musser et :11.
`5141314
`5,212,182
`611993 Fialdwin et :11.
`.. 5141252
`5,215,989
`311904 Martin et al.
`.
`5461201
`5,292,883
`411995 Baroni ................................... .. 5441334
`5,410,057
`611990 Masuda et at.
`....................... .. 5141255
`5,527,801
`FOREIGN PATENT DOCUMENTS
`
`
`
`0534445112
`0543057111
`49109359
`97093105 775
`99095140540
`
`311994
`311995
`1011974
`911991
`1211995
`
`.
`European Pat. 011.
`European Pat. Off. .
`Japan .
`Wll-’() .
`WIPO .
`
`1 01123
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,885,983
`Page 2
`
`OTHER PUBLICATIONS
`
`Morton, RI-'.. et al., J. Biol. Chem. 256, 1992-1995 (1981),
`“A Plasma Inhibitor oi" 'I'riglyeer‘ide and (Ihloesteryl Ester
`'l'ransfer Activities".
`
`Wetterau, J. et a1., Biochcm: 30, 44-[I6-I412 (1991): "Struc-
`tural Properties of the Mierosomal
`'[‘riglyocride—'l‘ransfcr
`Protein Complex”.
`Wellcrau, J. et £11., J. Biol. Chem. 265, 9800-980?‘ (1990).
`"Protein Disulfitle Isomerasc Is
`a Component of
`the
`Microsornal Triglyceride 'l‘ransier Protein (.‘ornplex”.
`Wetterau, J. and Zilversmit, D.B., Chem, and Phys. of
`Lipids 38, 205-22 (1985). “Purification and Characteriza-
`tion of Microsomal Triglyceride and Cholesleryl Ester
`Transfer Protein From Bovine Liver Mierosomes”.
`
`Wetterau,.]. and Zi1versmit,]).I-3., Biochimicia et Biophysica
`Acta 875, 610-61? (1986). “Ixiealization of intracellular
`triaeylglyoerol and eholesteryl ester transfer activity in rat
`tissues”.
`Wetterau, J. and Zilvcrsmit, D.B., J. Biol. Chem. 259,
`1[l863—1[l866 (1984) “A'I‘riglyeeride and (Tholesteryl Ester
`Transfer Protein Associated with Liver Mierosonies”.
`
`Wetterau, J ., Grant Application entitled: "Intracellular Trig-
`lyceride Transport and Metabolism".
`
`Presentation Materials, Aspen Bile /\eid;’('holesterol
`ferenee, Aug. 15, 1992.
`
`(Ton-
`
`Wetterau, J. R., et al., Science, vol. 258, 999-1001, Nov. 6,
`1992, “Absence of Microsomal 'liiglyceride Transfer Pro-
`tein in Individuals with Abetalipoproteinemia”.
`
`Archibald, J. L., et al., Journal of Medicinal Chemistry, Vol.
`14, No. 11, pp. -1054 1059.
`
`(fortim, L. et al., J. Med. Chem, 34, pp. 2242-2247‘, 1991.
`
`Hall, I. H. et al,,l’harmaeeutical Resc-areh,vol. 9, No. 10, pp.
`1324-1329, 1992.
`
`Hall, I. ll., et al., Pltarmaeological Research Communica-
`tions, vol. 19, No. 12, pp. 839-858, "1987.
`
`Murthy el al., Eur. J. Med. Chern.—C'him. Ther., vol. 20, No.
`6, pp. 547-550, 1985.
`
`2ul'l23
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,885,983
`
`1
`INHIBITORS OF MICROSOMAI.
`TRIGLYCERIDE TRANSFER PROTEIN AND
`METHOI)
`
`This application claims the benefit of the provisional
`application 603017254, filed on May [0, I996.
`
`FIELD O15 Tilli [NVL-'N'l'IOl\|
`
`This invention relates to novel compounds which inhibit
`microsomal triglyceridc- transfer protein, and to methods for
`decreasing serum lipids and treating atherosclerosis employ-
`ing such compounds.
`BACKGROUND 01‘ TIIl_i INVl.iN'l'l0N
`
`The mierosomal triglyceride transfer protein (MTP) cata-
`lyzes the transport of triglyceride (TU), cholesteryl ester
`(CE), and phosphatidylcholine (PC) between small unila-
`mellar vesicles (SUV). Wetterau & Zilversmit, Client. Pl'i_vs.
`l'.ipia'.s' 38, 205-22 (1985). When transfer rates are expressed
`as the percent of the donor lipid transferred per time, MTP
`expresses a distinct preference for neutral
`lipid transport
`[TE and CE), relative to phospho lipid transport. The protein
`from bovine liver has been isolated and characterized.
`Wetterau & Zilversmit, Chem. Phys. Lipids 38, 205-22
`(1985). Polyacrylamide gel electrophoresis (PAGE) analysis
`of the purified protein suggests that the transfer protein is a
`complex of two subunits of apparent molecular weights
`58,000 and 88,000, since a single band was present when
`purilied MTP was electro—phoresed under nondenaturing
`condition, while two bands of apparent molecular weights
`58,000 and 88,000 were identified when electrophoresis was
`performed in the presence of sodium dodeeyl sulfate [SDS).
`These two polypeptides are hereinafter referred to as 58 kDa
`and 88 k[)a, respectively, or the 58 k[)a and the 88 k[)a
`component of MTP, respectively, or the low molecular
`weight subunit and the high molecular weight subunit of
`MTP, respectively.
`Characterization of the 58,000 molecular weight compo-
`nent of bovine MTP indicates that
`it
`is the previously
`characterized multifunctional protein, protein disultide
`isomerase (l-’l)l). Wetterau et al.,J. Biol’. Clteitr. 265, 9800-7
`(1990). The presence of PDI in the transfer protein is
`supported by evidence showing that (1) the amino terminal
`25 amino acids of the bovine 58,000 kDa component of
`MTP is identical to that of bovine PDI, and (2) disulfirlc
`isomerase activity was expressed by bovine MTP following
`the dissociation of the 58 kl'Ja-88 kDa protein complex. In
`addition, antibodies raised against bovine l-’I)I, a protein
`which by itself has no TG transfer activity, were able to
`immunoprecipitate bovine 'I‘(j transfer activity from a solu-
`tion containing purified bovine MTP.
`PDI normally plays a role in the folding and assembly of
`newly synthesized disultide bonded proteins within the
`lumen of the endoplasmic reticulum. Bulleid & Freedman,
`Nature 335, 649-51 (1988). It catalyzes the proper pairing
`of cysteine residues into disulfide bonds, thus catalyzing the
`proper folding of disulftde bonded proteins. In addition, PD]
`has been reported to be identical
`to the beta subunit of
`human prolyl 4-hydroxylase. Koivu et al., J. Biol. Chem.
`262, 6447-9 (1987). The role of P131 in the bovine transfer
`protein is not clear.
`It does appear
`to be an essential
`component of the transfer protein as dissociation of PD]
`from the 88 k[)a component of bovine MTP by either low
`concentrations ofa denaturant (guanidine IICI), a chaotropic
`agent (sodium perchlorate), or a nondenaturing detergent
`(octyl glucoside) results in a loss of transfer activity. Wet-
`
`10
`
`I5
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`Isolated
`terau et al., Bios.-’temi.sfry 30, 9728-35 (1991).
`bovine PDI has no apparent lipid transfer activity, suggest-
`ing that either the 88 kDa polypeptide is the transfer protein
`or that it confers transfer activity to the protein complex.
`The tissue and subcellular distribution of MTP activity in
`rats has been investigated. Wetterau & Zilversmit, Br'()cI'icm.
`B£oph_v5..»tcta 875, 610-7 (1986). Lipid transfer activity was
`found in liver and intestine. Little or no transfer activity was
`found in plasma, brain, heart, or kidney. Within the liver,
`MTP was a soluble protein located within the lumen of the
`mierosomal fraction. Approximately equal concentrations
`were fou nrl in the smooth and rough microsomes.
`Abetalipoproteinemia is an autosomal recessive disease
`characterized by a virtual absence of plasma lipoproteins
`which contain apolipoprotein B (apoB). Kane & Ilavel in
`The Metabolic Brisis of Inlierired Disease, Sixth Edition,
`1139-64 (1989). Plasma '1‘G levels may be as low as a few
`mgfdl., and they fail
`to rise after fat
`ingestion. Plasma
`cholesterol levels are often only 20-45 mgjdI_. These abnor-
`malities are the result of a genetic defect in the assembly
`andtor secretion of very low density lipoproteins (VLDL) in
`the liver and chylomicrons in the intestine. The molecular
`basis for this defect has not been previously determined. In
`subjects examined, triglyceride, phospholipid, and choles-
`terol synthesis appear normal. At autopsy, subjects are free
`of atherosclerosis. Sehaefer et al., Clirt. Chem. 34, 139-12
`(1988). A link between the apoB gene and abetalipopro—
`teinemia has been excluded in several families. Talmud et
`
`al.,.}’. Cfin. Imresr. 82, 1803-6 (1988) and Huang et al.,Am.
`J. limit. Genet. 46, 1141-8 (1990).
`Subjects with abetalipoproteinemia are afflicted with
`numerous maladies. Kane & Havel, supra. Subjects have fat
`malabsorption and TG accumulation in their enterocytes and
`hepatoeytes. Due to the absence of T(}—rieh plasma
`lipoproteins, there is a defect in the transport of fat-soluble
`vitamins such as vitamin E. This results in acanthocytosis of
`erythrocytes, spinocerebellar ataxia with degeneration of the
`fasciculus cuneatus and gracilis, peripheral neuropathy,
`degenerative pigmentary retinopathy. and eeroid myopathy.
`Treatment of abetalipoproteinemic subjects includes dietary
`restriction of fat
`intake and dietaiy supplementation with
`vitamins A, 1:" and K.
`
`In vitro, MTP catalyzes the transport of lipid molecules
`between phospholipid membranes. Presumably,
`it plays a
`similar role in vivo, and thus plays some role in lipid
`metabolism. The subcellular (lumen of the microsomal
`fraction) and tissue distribution (liver and intestine) of MTP
`have led to speculation that it plays a role in the assembly of
`plasma lipoproteins, as these are the sites of plasma lipo-
`protein assembly. Wetterau & Zilversmit, Bioelteitt. Br'opltys'.
`Actr: 875, 610-7 (1986). The ability of MTP to catalyze the
`transport of TG between membranes is consistent with this
`hypothesis, and suggests that MTP may catalyze the trans-
`port of TG from its site of synthesis in the endoplasmic
`reticulum (ER) membrane to nascent lipoprotein particles
`within the lumen of the ER.
`
`Olofsson and oolleagttes have studied lipoprotein assem-
`bly in IIepG2 cells. Bostrom et al., J. Biol. Client. 263,
`4434-42 (1988). Their results suggest small precursor lipo-
`proteins become larger with time. This would be consistent
`with the addition or transfer of lipid molecules to nascent
`lipoproteins as they are assembled. MTP may play a role in
`this process.
`In support of this hypothesis, Howell and
`Palade, J. Cch’ Biol. 92, 833-45 (1982),
`isolated nascent
`lipoproteins from the hepatic Golgi fraction of rat
`liver.
`There was a spectrum of sizes of particles present with
`
`3 ufl23
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`4
`_C0m{nu¢d
`
`0
`A
`/
`
`Rf‘
`
`N
`
`R5
`
`0,
`
`0
`
`_\,]_R].’
`
`R.
`
`K N/
`/5' \/
`
`Y
`
`R3
`
`R,
`
`/
`
`1“
`
`5,885,983
`
`3
`varying lipid and protein compositions. Particles of high
`density lipoprotein (HDL) density, yet containing apoB,
`were found. Higgins and Ilutson, J.
`Ijplid Res’. 25,
`1295-1305 (1984),
`reported lipoproteins isolated from
`Golgi were consistently larger than those from the en(|o-
`plasmic reticulum, again suggesting the assembly of |ipo-
`proteins is a progressive event.
`
`5
`
`Recent reports (Science, Vol. 258, page 999, I992; I).
`Sharp et. al., Nature, Vol. 365, page 65, 1993) demonstrate
`that the defect causing abetalipoproteinemia is in the M11’
`gene, and as a result, the M11’ protein. Individuals with
`ahetalipoproteinemia have no M'l'P activity, as a result of
`mutations in the MTP gene, some of which have been
`characterized. These results indicate that MT!’ is required for H
`the synthesis of apoB containing Iipoproteins, such as
`' whom
`VIDL,
`the precursor to IDI..
`It
`therefore follows that
`inhibitors of MTP would inhibit the synthesis of VI .|)I. and
`l.[)I., thereby lowering V[_[)[. levels, IDI. levels, choles-
`an
`terol levels, and triglyceride levels in animals and man.
`Canadian Patent Application No. 2,091,102 published H
`Mar. 2, 1994 [corrcsputlditlg to U.S. application Set. No.
`117,362,
`llled Sep. 3, 1993 (tile l)(T2lh)), U.S. Pat. No.
`5,595,872 reports MTP inhibitors which also block the
`production of ap0B containing lipoproteins in a human 35
`hepatic cell line (llep(32 cells). This providesfurther support
`for the proposal that an MTP inhibitor would lower apoR
`containing lipoprotein and lipid levels in vivo. This Cana-
`dian patent application discloses a method for identifying
`the MTP inhibitors
`
`1U
`
`3::
`
`X is:
`
`CH-R“, —V|—‘H—fi—‘H
`R"
`R1”
`
`01
`
`-3- = |-—'
`R9 R1“
`
`3
`o
`1
`10
`_
`.
`_
`_
`_
`fuzclé 1"“;“I: D “I” ;':‘l‘,'P°’a“rl"’l‘;ll3’k
`helflroiglaui llircycioalkyl’ or
`cl0a31'k’1a1k ll
`_
`'
`y ‘
`y
`Y ’
`y
`Y ‘
`Y 15
`
`F
`
`y
`
`_(C”-’-’'’'_ ‘” _fi_
`0
`
`II
`
`m
`
`,
`
`‘
`
`’
`
`N
`
`\_
`'
`
`0
`
`which has the name 2-L1_(3, 3_(|iphchy1p;opy1)_4_
`piperidinyl]-2, 3-dihydro-3-oxo-III-isoindole hydrochloride
`and
`
`O
`
`1,
`
`N \/
`
`ocu;
`
`35
`
`40
`
`45
`
`5h
`
`which has the name 1—[3—((J—fluoro—l—tetralanyl)methyl]—4—
`(J-rnethoxyphenyl piperazine
`EP 064305 7A1 published Mar. L5, 1995, discloses MT1’ 55
`inhibitors of the structure
`
`
`
`N
`
`N_R1
`
`1
`
`6”
`
`65
`
`4 "T123
`
`where m is 2 or 3;
`
`R‘
`
`is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl
`(wherein alkyl has at
`least 2 carbons), diarylalkyl,
`arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalkyl (wherein alkyl has at
`least 2 carbons), eyeloalkyl, or eycloalkylalkyl
`(wherein alkyl has at
`least 2 carbons); all of the
`aforementioned R‘ groups being optionally substituted
`through available carbon atoms with 1, 2, or 3 groups
`selected from halo, haloalkyl, alkyl, alkenyl, alkoxy,
`aryloxy. aryl. arylalkyl. alkyl-mcrcapto, arylmcrcaptn,
`eycloalkyl, cycloalkyl-alkyl, heteroaryl,
`rluorenyl,
`heteroarylalkyl, hydroxy or oxo; or
`R1 is a group of the structure
`R '
`
`R15
`
`"R1;
`
`R J
`L
`
`Z
`
`RI:
`
`R14
`
`R” is 21 hand, alkylenc, alkcnylcnc or alkynylenc of up to
`ti carbon atotns, arylene (for example
`
`1-
`
`PENN EX. 2212
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,885,983
`
`6
`definitions). Ihiol, alkylthio, arylthio, heteroarylthio,
`arylthioalkyl, alkylearbonyl, arylearbonyl,
`arylaminoearhonyl, alkoxycarbonyl, aminoearbonyl,
`alkynylarninoearbonyl, alkylaminocarhonyl,
`aIkenylaniinocarbonyl, alkylcarbonyloxy,
`arylearbonyloxy,
`alkylearbonylarrtino,
`arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,
`arylsulfonyl, alkylsulfonyl, arylsulfonylamino; with
`the provisothat when R5 is (I113, R" is not 11; and where
`R5 is phenyl, the phenyl preferably includes an ortho
`hydrophobic substituenl such as alkyl, halozllltyl, ztryl,
`aryloxy or arylalkyl;
`R6 is hydrogen or C1 C4 alkyl or C1 C4 alkenyl;
`R’ is alkyl, aryl or arylalkyl wherein alkyl or the alkyl
`portion is optionally substituted with oxo; and
`including pharmaeeutieally acceptable salts and anions
`thereof.
`
`In the formula I compounds, where X is CH: and R3, R3
`and R4 are each II, R1 will be otherthan 3,3-diphenylpropyl.
`In the fnrmllla III compounds, where one of R3, R3 and R4
`is t')—lluoro, and the others are II, R7 will be other than
`4-O-methoxyphenyl.
`US. application Ser. No. 472,067, filed Jun. 6, 1995 (file
`DC21e), U.S. Pat. No. 5,739,135 discloses compounds of
`the structure
`
`N— R‘,
`
`RI
`
`IN
`
`it!
`
`R
`
`R‘/
`
`0
`
`Ix
`
`x
`
`01'
`
`
`
`RI
`|
`N
`
`or
`
`UT
`
`Q
`R5’ \
`INR6
`
`R3
`
`0
`
`R‘;
`
`/R4
`
`where Q is
`
`R1
`
`W N/
`/N X)
`
`Y
`
`0
`D
`ll
`II
`—t'.f— or —S—'.
`
`5
`or mixed arylene—a]kylene (for example
`
`(9-lT;)..’)
`
`where n is 1 to 6;
`
`R12 is hydrogen, alkyl, alkenyl, aryl, heteroaryl,
`haloalkyl, arylalkyl, arylalkenyl, cyeloalkyl, aryloxy,
`alkoxy, arylalkoxy, heteroarylalkyl or eyeloalkylalkyl;
`Z is a bond, 0, S, N—alkyl, N—aryI, or alkylene or alk-
`enylene of from 1 to 5 carbon atoms;
`R13, R”, R”, and R1" are independently hydrogen, alkyl,
`halo, haloalkyl, aryl, eyeloalkyl, eycloheteroalkyl,
`alkenyl, alkynyl, hytlroxy, alkoxy, nitro, amino, thio,
`all\'ylsull‘onyl, arylsullonyl, alkylthio, arylthio, carhoxy,
`aminocarhonyl, alkylcarbonyloxy, all(ylcarhonyl—
`arnino, arylalkyl, heteroaryl, heteroarylalkyl, or ary-
`loxy;
`or R1 is
`
`- [C-Hxlp /<
`
`RI.
`
`R18
`
`wherein p is 1 to 8 and R17 and R18 are each indepen-
`dently II, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cyeloalkylalkyl, at least
`one of R” and RH being other than II;
`or R1 is
`
`RN}
`_R19_< RBI
`
`wherein R19 is aryl or heteroaryl;
`R2” is aryl or heteroaryl;
`R21 is II, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, heteroarylalkyl,
`heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or
`eyeloalkylalkoxyg
`R3, R3, R4 are independently hydrogen, halo, alkyl,
`hnloalkyl, alkcnyl, ztlkoxy, atryloxy, aryl, arylalkyl,
`alkylmereapto. arylmereapto, eyeloalkyl,
`cycloalltylalkyl, heteroaryl, heteroaryla lkyl, hydroxy or
`haloalkyl;
`R5 is alkyl of at least 2 carbons, alkenyl, alkynyl, aryl,
`heteroaryl, arylalkyl, heteroarylalkyl, eyeloalkyl,
`eyeloalkylalkyl, polycycloalkyl, polycycloalkylalkyl,
`eyeloalkenyl, eyeloalkenylalkyl, polycyeloalkenyl,
`polycycloalkenylalkyl, heteroarylcarbonyl, all of the
`R5 and R5 substituents being optionally substituted
`through available carbon atoms with "l, 2, or 3 groups
`selected from hydrogen, halo, alkyl, haloalkyl, alkoxy,
`haloalkoxy, alkenyl, alkynyl, cycloalkyl,
`eycloalkylalkyl, eyeloheteroalkyl, eycloheteroalky—
`lalkyl, aryl, heteroaryl, arylalkyl, arylcyclo-alkyl,
`arylalkynyl, aryloxy, aryloxyalkyl, aryl—alkoxy,
`arylazo, heteroaryloxo, heteroarylalkyl,
`heteroarylalkenyl, heteroaryloxy, hydroxy, nitro,
`eyano, amino, substituted amino (wherein the amino
`includes 1 or 2 substituents which are alkyl, or aryl or
`any of the other aryl compounds mentioned in the
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`till
`
`65
`
`5ul'l23
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`X l5
`
`7
`
`5,885,983
`
`8
`—eontinued
`
`R15
`
`or
`
`or
`
`UT
`
`
`
`_R”_zl
`
`H
`R _;,'_.:‘;
`
`A 1
`(a =“’ ” 014]
`
`R.‘
`
`R”
`
`-R“—7“
`
`Ru_Z2
`
`R15»:
`
`R16“
`
`R14
`
`R1‘):
`
`R15:
`
`',U[
`
`R“
`
`1
`-
`-
`'\
`,
`.
`'\
`R is an tndcnyl type group of the structure
`R13
`
`L)
`
`5
`
`F
`
`(1
`
`H
`
`CIIR5_.—fi—_.—(|:[I—(|3[I— or —(|3=(|L‘—:
`0
`R9
`R10
`R9 RID
`
`R8, R9 and R10 are independently hydrogen, alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
`Y is
`
`_(CH2]m_
`
`or _ii_
`0
`
`5
`
`10
`
`15
`
`wherein m is 2 or 3;
`
`R1 is alkyl, alkenyl, alkynyl, aryl, hcteroaryl, arylalkyl
`wherein alkyl has at
`least 2 carbons, diarylalkyl,
`
`an
`”
`
`arylalkenyl, diarylalkenyl, arylalkynyl, rliarylalkynyl,
`diatylalkylaryl, heteroarylalkyl wherein alkyl has at
`least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein
`alkyl has at least 2 carbons, all optionally substituted 35
`through available carbon atoms with 1, 2, 3 or4 groups
`selected from halo, haloalkyl, alkyl, alkcnyl, alkoxy,
`aryloxy, aryl, arylalkyl, alkylmercapto, arylmercaplo,
`cycloalkyl. cyclo-alkylalkyl, heteroaryl, Iluorenyl,
`heteroarylalkyl. hydroxy or oxo;
`
`3”
`
`or R1 is a Iluorenyl-type group ol‘ the structure
`
`A
`
`B
`
`as
`
`40
`
`‘U
`
`55
`
`(T
`
`6”
`
`65
`
`R13
`
`RH
`
`R1641
`
`Rlfie:
`
`_Rtl_zl
`
`RtI_;2
`
`Z1 and Z3 are the same or diiferent and are independently
`a bond, 0, S,
`
`5;,
`II
`0
`
`_.
`
`S
`(II)
`0 ,
`
`NII
`
`C __
`II
`0
`
`C _.
`N
`I
`II
`alkyl 0
`
`F
`II
`0
`
`m'
`
`H
`C‘
`I
`on
`
`with the proviso that with respect to B, at least one of
`Z' and Z2 will be other than a bond; R” is a bond,
`alkylene, alkenylene or alkyriylene of up to 10 carbon
`atoms; arylerie or mixed arylene-alkylene; R“ is
`hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl,
`trihaloalkylalkyl, helc-roaryl, heteroarylalkyl, arylalkyl,
`arylalkenyl, cyclo-alkyl, aryloxy, alkoxy, arylalkoxy or
`cycloalkyl-allay], with the provisos that
`
`6 0f123
`
`PENN Ex. 2212
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,885,983
`
`10
`aryloxyalkyl, arylalkoxy, arylaze, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`Iiydroxy, nitro, cyano, amino, substituted amino, thiol,
`alkylthio, arylthio, heteroarylthio, arylthioalkyl,
`alkylcarbonyl, arylcarbonyl, arylaminocarbonyl,
`alkoxycarbonyl.
`arninocarbonyl,
`alkynylamiiiocarlmiiyl, alkylaminocarlionyl,
`alkenylaminoearbonyl, alkylearbonyloxy,
`arylcarbonyloxy,
`alkylcarbonylarnino,
`arylcarbonylamino, arylsullinyl, arylsulflnylalkyl,
`arylsulfonyl, alkylsulfonyl, arylsulfoiiylamitio,
`heteroarylearbonylamino, heteroarylsulfinyl,
`heleroarylthio, heteroarylsulfonyl, alkylsulfinyl;
`R6 is hydrogen or C1-C4 alkyl or C1-C4 alkenyl; all
`optionally substituted with 1, 2, 3 or 4 groups which
`may independently be any of the substituents listed in
`the definition of R5 set out above;
`R7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as
`part of arylalkyl is optionally substituted with mm
`
`are the same or ditferenl and are independently selected
`from heteroaryl containing 5- or 6—ring members; and
`N-oxides.
`
`O
`
`N/
`-.R,
`
`thereof; and
`pharmaceutically acceptable salts thereof; with the pro-
`visos that where in the lirst formula X is C112, and R3,
`R3 and R" are each 11,
`then R1 will be other than
`3,3—diphenylprnpyl, and in the fifth formula, where one
`o1‘R2, R3 and R" is 6—fluoro, and the others are II, ll?
`will be other than 4-(2-methoxyphenyl).
`U.S. application Ser. No. 548,811 filed Jan. 11, I996 (file
`DC21h), discloses compounds having the structure
`XI
`
`0|
`
`11
`|
`('T—.\'—f_‘H3—f_‘l~‘;
`
`2
`
`(r_*n_.),—i~'
`
`if
`I\'—(_‘—R-“
`[I
`
`X!
`
`including the piperidine N-oxide thereof or a pharmaceuti-
`eally acceptable salt thereof. wherein Z is a bond, 0 or S;
`
`9
`(1) when R” is H, aryloxy, alkoxy or
`
`—NII—C—_. —:~i—C—, —c—
`ll
`l
`ll
`ll
`0
`alkyl 0
`0
`
`or arylalkoxy, then Z2 is a bond and
`(2) when Z:
`is a bond, Rm cannot be heteroaryl or
`heteroarylalkyl;
`Z is bond, 0, S, N—alkyl, N—aryl, or alkylene or alkcnylcne
`from 1
`to 5 carbon atoms; R”, R”, R”, and R” are
`independently hydrogen. alkyl, halo, haloalkyl, aryl.
`cycloalkyl, cyclo-heteroalkyl, alkenyl, alkynyl,
`hydroxy, alkoxy, nitro, amino,
`thio, alkylsulfonyl,
`arylsulfonyl, alkylthio, arylthio, aminocarbonyl,
`alkylcarbonyloxy,
`arylcarbonylarnino,
`alkylcarbonylamino, arylalkyl, hetcroaryl, heter0aryla-
`lkyl or aryloxy;
`R15" and Rm” are independently hydrogen, alkyl, halo,
`haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl,
`alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl. alkylthio,
`arylthio, aniinocarbonyl, alkylcarbonyloxy,
`arylcarbonylarnino, alkylcarbonylamino, arylalkyl,
`heteroaryl, heteroarylalkyl, or aryloxy;
`or R1 is a group of tlic structure
`RI.
`
`—EC[1':Jp —<
`
`R18
`
`wherein p is 1 to 8 and R” and R18 are each indepen-
`dently II, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least
`one of R” and RH being other than II;
`or R] is a group of the structure
`
`wherein R19 is aryl or heteroaryl;
`R30 is aryl or heteroaryl;
`R“ is
`II, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, heteroarylalkyl,
`lieteroarylalkoxy, cycloalltyl, cycloalkylalkyl or
`cycloalkylalkoxy;
`R3, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylrnercaplo,
`arylrnereapto, cycloalkyl, cycloalkylalliyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`R5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy,
`aryloxy, arylalkoxy, heteroaryl, arylalkyl,
`hetcroarylalkyl, cycloalkyl, cycloalkylalkyl,
`polyeycloalkyl, polyeyclealkylalkyl, eyeloalkenyl,
`eycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl,
`polycyeloalkenyl, polyeycloalkeuylalkyl,
`heteroarylcarhonyl, amino, alkylamino, arylarnino,
`heternarylamino, eycloalkyloxy, cycloalkylamino, all
`optionally substituted through available carbon atoms
`with I, 2, 3 or 4 groups selected from hydrogen, halo,
`alkyl, haloalkyl, alkexy, haloalkoxy, alkcnyl, alkynyl,
`cycloalkyl, cycloalkylalkyl, cycloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`arylcycloalkyl, arylallienyl, arylalkynyl, aryloxy,
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`7ufl23
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`11
`
`12
`
`5,885,983
`
`X1 and X‘ are independently selected from H or halo;
`
`R1 is a fluorenyl—type group of the structure
`
`R16
`
`_R11_£l
`
`Rl_J_/_
`
`7'.
`
`or
`
`or
`
` _Rll
`
`“II
`
`Rt; R“
`
`A
`
`R;
`
`B
`
`I6
`
`R
`
`_R11_z1
`
`Rl2_z2
`
`15
`
`R
`
`RIG
`
`R15
`
`Z
`
`or
`
`_R11_z1
`
`R12_z2
`
`Z
`
`: or
`
`R”
`
`C
`
`R14
`
`R”
`
`R14
`
`D
`
`R‘ is an intlenyl—type group of the structure
`
`R13
`
`R14
`
`RI!
`
`R14
`
`x is an integer from 2 to 6:
`
`R5 is heteroaryl, aryl, helerocycloalkyl or cyeloalkyl, each
`R5 group being optionally substituted with l, 2, 3 or 4 5
`substituenls which may be the same or dillierent.
`
`1tJ
`
`I5
`
`an
`
`15
`
`3::
`
`SUMMARY OF THE INVENTION
`
`.
`.
`.
`invention, novel com-
`In accordance with the present
`pounds are provided which are inhibitors of MTP and have
`the structure
`
`
`
`N—Rl:
`
`or
`
`[I
`
`\—1<1
`
`.\'—(ctt_»;,
`F)
`
`IR
`
`/O\
`
`R5
`
`whereQis
`
`<1
`0
`II
`II
`—(T— or —S—
`II
`0
`
`Xis:CIIR",
`
`—(.‘—. —(.‘l-I—(.‘H— or —(.‘=(.‘—:
`
`II
`(J
`
`I
`R9
`
`I
`R_l[|
`
`I
`I
`R9 RJIJ
`
`n is O or '1; R“, R“ and R1“ are independently hydrogen.
`alkyl, alkenyl, allrynyl, aryl, arylalkyl, heleroaryl,
`heteroarylalkyl, cyclrtalkyl, or cycloalkylalkyl;
`
`35
`
`4e
`
`45
`
`5U
`
`_Rll_zl
`
`Ru—
`RH:
`
`(CH7Ja
`E
`(a = 2, 3 or 4-)
`
`or
`
`_Rl]_zl
`
`R163
`
`RI2_Z2
`
`Rm
`F
`
`R13
`
`Rn
`
`R14
`
`_Rl1_z1
`
`91'
`
`R"—Z‘
`Rlfia
`
`C
`
`(
`
`-
`
`G
`
`Rlba
`
`_R1I_z1 QR12_Z2
`
`R15...
`H
`
`or
`
`R169
`
`RI-I
`
`'-
`
`Rlsa
`
`Z1 and Z: are the same or different and are independently
`a bond, 0, S,
`
`_.
`
`NH t‘.
`
`_.
`
`N
`
`C .
`
`F
`
`nr
`
`D—"5I
`
`II
`
`sI
`
`t0
`
`(‘
`
`with the proviso that with respect to B, at least one of
`Z' and Z: will be other than a bond;
`
`R“ is a bond, alkylene, alkenylene or alkynylene of up to
`10 Carbon atoms, arylene (let example
`
`R1 is alkyl, alkenyl, £ll.l'\'.)«’l'lyl, aryl, heteroaryl, arylallxyl
`[wherein alkyl preferably has at least 2 carbons, more
`preferably at least 3 carbons}, diarylalkyl, arylalkenyl, 55
`diarylalkenyl, arylalkynyl, diarylalkynyl,
`diarylalkylaryl, heteroarylalkyl (wherein alky] prefer-
`ably has at least 2 carbons, more preferably at least 3
`carbons), cycloalkyl, or cyeloalkylalkyl (wherein alkyl
`preferably has at least 2 carbons, more preferably at
`least 3 carbons); all of the aforementioned R‘ groups
`being optionally substituted through available carbon
`atoms with '1, 2, 3 or 4 groups selected from halo,
`haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl,
`arylalkyl, alkyl-rnercapto, arylrnercaplo, eycloalkyl, 65
`cycloalkyl-alkyl, heleroaryl, Iluorenyl, heteroarylalkyl,
`hydro:-ry or 0x0; or
`
`at:
`
`8ul'l23
`
`PENN EX. 2212
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,885,983
`
`13
`
`or mixed arylene-alkylene (for example
`
`(( Tl Ig)q— J
`
`to 6;
`where q is l
`lialoalkyl,
`R1?‘
`is liydrogeti, alkyl, alkenyl, aryl,
`trihaloalkyl,
`trihaloalkylalkyl, hcteroaryl,
`heteroarylalkyl, arylalkyl, arylalkcnyl, cyclo—alkyl,
`aryloxy, alkoxy, arylalkoxy or eyeloalkyl-alkyl; with
`the provisos that (1) when R‘: is H, aryloxy, alkoxy or
`arylalkoxy, then Z2 is
`
`—NH—c—_. —N—c'—, —C—
`II
`I
`II
`II
`o
`arty: o
`0
`
`or a bond;
`and (2) when Z2 is a bond, R12 cannot be heteroaryl or
`heteroarylalkyl;
`Z is a bond. 0, S, N—alkyl, N—aryl, or alkylene or alk-
`enylene of from 1 to 5 carbon atoms;
`R”, R“, R”, and R” are independently hydrogen. alkyl,
`halo, haloalkyl, aryl, cyeloalkyl, cyelohcteroalkyl,
`alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio,
`all\'ylsull‘onyl, arylsulfonyl, alkylthio, arylthio,
`amiriocarbonyl, alkylcarhonyloxy, arylcarbonylarnino,
`alkylearbonylamino, arylalkyl, heteroaryl,
`heteroarylalkyl, or aryloxy;
`R15" and Rm" are independently any of the R15 or R”
`groups except hydroxy, nitro, amino or thio;
`or R’ is
`
`R"
`
`‘R18
`
`—[C[I-_»],,—<
`
`wherein p is '1 Lo 8 and R” and R” are each indepen-
`dently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl,
`heteroarylalkyl, cycloalkyl or cyeloalkylalkyl, at least
`one of R17 and R18 being other than II;
`or R1 is
`
`R30
`_R19:< RBI
`
`wherein R1" is aryl or heteroaryl;
`R2” is aryl or heteroaryl;
`R31 is II, alkyl, aryl, alkylaryl, arylalkyl, aryloxy,
`arylalkoxy, heteroaryl, hetcroarylalkyl,
`heteroarylalkoxy, eycloalkyl, eycloalkylalkyl or
`eyeloalkylalkoxy;
`R3, R3, R4 are independently hydrogen, halo, alkyl,
`alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercaplo,
`arylmereapto, cyeloalkyl, eycloalkylalkyl, heteroaryl,
`heteroarylalkyl, hydroxy or haloalkyl;
`
`1U
`
`I5
`
`30
`
`35
`
`4U
`
`45
`
`SU
`
`55
`
`6E]
`
`65
`
`R’
`
`14
`, alkenyl, alkynyl, aryl, alkoxy, aryloxy,
`is alkyl
`arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl,
`eyeloalkyl, eyeloheteroalkyl, heteroaryloxy,
`eyeloalkylalkyl, polycycloalkyl, polyeyeloalkylalkyl,
`cycloalkenyl, cycloalkenylalkyl, polyeycloalkenyl,
`polyeyeloalkenylalkyl, heteroaryls.'arbonyl, amino,
`alkylamirio, arylamino, heteroarylamino,
`eyeloalkyloxy, cycloalkylamino, all of the R5 substitu-
`enls and R6 substituents (set out hereinafter) being
`optionally substituted through available carbon atoms
`with "l, 2, 3 or 4 groups selected from hydrogen, halo,
`alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,
`cyeloalkyl, cycloalkylalkyl, cyeloheteroalkyl,
`cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,
`aryleycloalkyl, arylalkenyl, arylalkynyl, aryloxy,
`aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo,
`heteroarylalkyl, heteroarylalkenyl, heteroaryloxy,
`hydroxy, nitro, eyano, amino, substituted amino
`(wherein the amino includes 1 or 2 substituents which
`are alkyl, aryl or heteroaryl, or any of the other aryl
`compounds mentioned in the definitions),
`thiol,
`alkylthio, arylthio, heteroarylthio, arylthioalkyl,
`alkylcarboriyl, arylearbonyl, arylaminoearbonyl,
`alkoxyearbonyl,
`aminocarbonyl,
`alkynylamirioearbortyl, alkylaminoearhonyl,
`alkenylaminocarbonyl, alkylcarbonyloxy,
`arylcarbonyloxy,
`alkylcarbonylami